Cephalosporin compounds of formula (II) are generally synthesised by two methods as described in the art. Both the methods involve amidification of the 7-amino function of the corresponding 3-(un)substituted cephalosporin derivative either directly with a 2-(2-amino thiazol-4-yl)-2-oxyimino acetic acid derivative (Method-I) or via Method-II a 4-halo-2-oxyimino-butyric acid derivative to give a 7-substituted cephalosporin addendum, which can be further elaborated to form the 2-(2-amino thiazol-4-yl)-2-oxyimino acetamido side chain and thereby, provide compounds of formula (II). The two methods of synthesis are summarized in Scheme-I.

In compounds of formula (III) of Method-I, the meanings of the groups X and R are as defined hereinearlier and the group Y is hydrogen or is a group which forms a basis that compound of formula (III) is in a reactive form. Similarly, in compound of formula (IV), of Method-II, the meanings of the groups X and R are as defined hereinearlier and the group Z is hydrogen or is a group which forms a basis that compound of formula (IV) is in a reactive form.
As per Method-I, synthesis of compound of formula (II) has been achieved by several ways, all differing in the choice of the reactive group Y. The following prior art methods illustrate the synthesis of compounds of formula (II) utilizing different reactive species as embodied in the group Y. These are to name a few;    i) U.S. Pat. No. 4,152,432 describes synthesis of cefotaxime comprising acylation of 7-aminocephalosporanic acid (7-ACA) with a compound of formula (III), wherein R is methyl and Y is a chlorine atom. In this method, the amino group of the thiazole ring is protected prior to amidification and subsequently deprotected by hydrolysis or hydrogenolysis.            Japanese Patent Nos. JP 52-102096, JP 53-157596 and British Patent No. GB 2 025 933 also utilize the same chemistry mentioned hereinbefore i. e. activation of the carboxylic acid as the acid halide. The acid halide, in particular the acid chloride is prepared by reaction of the 2-(2-amino thiazol-4-yl)-2-oxyimino acetic acid with PCl3, PCl5, SOCl2 or POCl3.        U.S. Pat. No. 3,954,745 also teaches a method for synthesis of cefazolin via the acid chloride method.            ii) Another method of activation of the carboxylic acid of formula (III), as disclosed in U.S. Pat. No. 5,317,099 is through formation of the activated ester by reaction of the carboxylic acid group with an acyloxyphosphonium chloride derivative. The method of preparation comprises reacting the carboxylic acid derivative (III) with triphenyl phosphine, hexachloroethane or carbon tetrachloride. However, this method increases the overall cost of the coupling reaction since it involves the use of expensive triphenyl phosphine.    iii) EP Patent Nos. EP 0 037 380 describes yet another method for synthesis of compounds of formula (II), specially cefotaxime and ceftriaxone, wherein the carboxylic acid group of compound (III) is activated as the benzothiazolyl thioester prior to formation of the amide bond at the 7-amino position. The benzothiazolyl thioester is turn prepared by reaction of the carboxylic acid compound (III) with bis[benzothiazolyl-(2)]disulfide and triphenyl phosphine, thereby rendering the method costly.    iv) U.S. Pat. No. 5,037,988 describes a process for production of compounds of formula (II), in particular, cefotaxime and ceftriaxone, in which the 2-(2-amino thiazol-4-yl)-2-oxyimino acetic acid (III) is activated as the dimethyl formiminium chloride chlorosulfite (DFCS) of formula (VI) and then coupled at the 7-amino position of the 3-substituted cephalosporin derivative to give compounds of formula (II).
                The dimethyl formiminium chloride chlorosulfite (VI), is in turn prepared by reacting equimnolar quantities of thionyl chloride and N,N-dimethylformamide at room temperature. The method however, suffers from drawbacks inter alia in that the reaction can be effected in only specific solvents like benzene and toluene.            v) U.S. Pat. No. 5,739,346 describes a process for synthesis of β-lactam derivatives such as cefotaxime and ceftriaxone wherein compound (III) is activated as an adduct with N,N dimethyl formiminium chloride chlorosulfite (DFCCS) of formula (VII), prior to 7-amidification to give compounds of formula (II).
    vi) WO 99/51607 discloses a process for preparation of cefixime, wherein 7-amino-3-vinyl-3-cephem-4-carboxylic acid is reacted with compound (III) activated as the benzothiazolyl thioester.    vi) U.S. Pat. No. 6,388,070 provides yet another variation, wherein the compound (III) is activated as a 2-mercapto-5-substituted-1,3,4-oxadiazole derivative prior to 7-amidification to give compounds of formula (II).
The amidification has also been achieved by activation of the carboxylic acid (III) by formation of its mixed anhydride, an active amide or an active ester, as disclosed in U.S. Pat. No. 4,409,214; as the thiophosphoryl ester, as disclosed in U.S. Pat. No. 5,567,813 for synthesis of cefixime, cefotaxime, ceftriaxone, cefepime, cefpirome sulfate, ceftizoxime etc.
Synthesis of compounds of formula (II) as per Method-II is equally widely documented in the literature. Several methods, varying subtly in the choice of the reactive group Z of compounds of formula (IV) have been utilised, albeit the choice of the activating group is primarily restricted to acid halides. A few of such methods are disclosed in:    a) U.S. Pat. No. 4,559,334, discloses a method for synthesis of cefdinir, wherein the carboxylic acid (IV) activated as the acid chloride is reacted with 7-amino-3-vinyl-3-cephem-4-carboxylic acid to give the 7-substituted addendum, which on reaction with thiourea gives cefdinir.    b) U.S. Pat. No. 4,409,214 discloses a method identical for synthesis of cefixime, a structurally similar analogue of cefdinir.    c) U.S. Pat. No. 5,109,131 describes an advantageous process for preparation of cephalosporin compounds using tert-butyl-3-oxobutyrate as an intermediate. The tert-butyl-3-oxobutyrate is used for preparation of the compound (IV), which is reacted as such or a reactive derivative thereof is reacted with a 3-substituted-7-amino cephalosporin compound to form the 7-substituted cephalosporin addendum, which on reaction with thiourea gives compounds of formula (II).            The reactive derivatives utilised for 7-amidification as disclosed in U.S. Pat. No. 5,109,131 include acid halides, a mixed acid anhydride, an active amide or an active ester.            c) European Patent No. 0 030 294 discloses a method for preparation of ceftriaxone comprising reaction of 4-bromo-2-methoxyimino-3-oxobutyric acid chloride with 7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic acid to give the 7-amino addendum, which is cyclized with thiourea to give ceftriaxone.    d) European Patent No. 0 842 937 claims a process for preparation of cefotaxime and ceftriaxone comprising reaction of 7-ACA and 7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic acid respectively with 4-chloro-2-methoxyimino-3-oxobutyric acid, activated as 2-mercaptobenzothiazolyl ester, followed by cyclisation of the intermediates thus obtained with thiourea to give cefotaxime and ceftriaxone respectively.    e) U.S. Pat. No. 4,960,766 discloses a method for acylation at the 7-amino position of a 3-substituted cephalosporin derivative by reaction with compound (IV), which is activated as an acid halide or as a mixed anhydride, an activated amide or an activated ester in the presence of dicyclohexylcarbodiimide or an organic or inorganic base to give the corresponding acylated compound. Formation of the thiazolyl ring is completed when the acylated compound thus obtained is reacted with thiourea.    f) EP Patent No. 0 556 768 describes a method for preparation of ceftriaxone comprising reaction of 7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic acid with 4-chloro-2-methoxyimino-3-oxobutyric acid, activated as 2-mercaptobenzothiazolyl ester, followed by cyclisation of the intermediate thus obtained with thiourea to give ceftriaxone . This patent claims that the abovementioned reaction and subsequent conversion of ceftriaxone to its disodium hemiheptahydrate salt can be carried out in one pot using a mixture of acetone and water as solvent.    g) U.S. Pat. No. 6,384,215 provides yet another variation, wherein the compound (Iv) is activated as a 2-mercapto-5-substituted-1,3,4oxadiazole derivative prior to 7-amidification to give compounds of formula (II) after cyclisation of the intermediate compound with thiourea.    h) U.S. Pat. No. 6,458,949 discloses a process for preparation of ceftiofur by reacting silylated 7-amino-3-(2-furylcarbonylthiomethyl)-3-cephem-4-carboxylic acid with 4-bromo/chloro-2-methoxyimino-3-oxobutyryl acid halide, followed by cyclization of the compound thus formed with thiourea.    i) Published U.S. Patent Application No. 2002/0128469 A1 claims an improved method for preparation of compounds of formula (II), specially cefotaxime and ceftriaxone comprising reaction of compound (V, see Scheme-I) with compound (IV) activated as a reactive derivative to give the corresponding intermediate 7-acylated compound, the improvement being reaction of the intermediate 7-acylated compound thus obtained is cyclized with silylated thiourea to form the aminothiazole ring.
Surprisingly, the present inventors have found a novel manner of activation of the carboxylic acid of 4-halogeno-2-oxyimino-3-oxobutyric acid of formula (IV), which provides novel reactive derivatives of formula (I).
Thus, it is an object of the present invention to provide novel reactive derivatives of formula I.
Yet further object of the present invention is to provide a simple and cost-effective method for preparation of cephalosporin compounds of formula (II) utilising compounds of formula (I).